Phebox ligands and methods of making same

ABSTRACT

The present disclosure provides compounds which are useful for a number of catalytic transformations of organic molecules, non-limiting examples including dehydrogenation of alkanes. The present disclosure further relates to methods of preparing the compounds of the present disclosure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Patent Application No. 62/993,154, filed Mar. 23, 2020, thecontents of which are incorporated by reference herein in theirentirety.

BACKGROUND

Phebox ligands are useful for developing metal complexes that catalyze awide variety of chemical reactions. These reactions include, forexample, conversion of low-value alkanes to high-value alkenes, orconversion of alkanes to other high-value unsaturated products such asaldehydes and alcohols. Other examples of the reactions that arecatalyzed by phebox based metal complexes are—Suzuki-Miyaura couplingreactions of aryl boronic acids and their derivatives with aryl halidesto give the corresponding biaryl products, enantioselective allylationof aldehydes, asymmetric Michael addition of α-cyanopropionates toacrolein, asymmetric reductive aldol reaction of aldehydes andα,β-unsaturated esters with hydrosilanes to give the correspondingβ-hydroxypropionates, and asymmetric alkynylation of α-ketoester withvarious aryl and alkyl substituted terminal alkynes to provide thecorresponding chiral tertiary propargylic alcohols.

However, despite their use in wide variety of reactions, there is stillan unmet need in the art to develop phebox ligands, which can becomplexed with metals to yield stable, convenient to synthesize, andhighly effective catalysts. The present disclosure addresses this unmetneed.

BRIEF SUMMARY OF THE INVENTION

The present disclosure provides, in part, certain compounds of formula(I), or a salt or solvate thereof:

wherein the various substituents in the compounds of formula (I) aredefined elsewhere herein. In one aspect, the compounds of the presentdisclosure are useful for a number of catalytic transformations oforganic molecules, including transformations of alkanes generallyrequiring harsh conditions (e.g. dehydrogenation). The presentdisclosure further relates to methods of preparing compounds of formula(I).

BRIEF DESCRIPTION OF THE FIGURES

The drawings illustrate generally, by way of example, but not by way oflimitation, various embodiments of the present application.

FIG. 1 shows the structure of the compound of Formula (I), in accordancewith various embodiments.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of thedisclosed subject matter. While the disclosed subject matter will bedescribed in conjunction with the enumerated claims, it will beunderstood that the exemplified subject matter is not intended to limitthe claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should beinterpreted in a flexible manner to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. For example, a range of “about 0.1% to about 5%” or “about 0.1%to 5%” should be interpreted to include not just about 0.1% to about 5%,but also the individual values (e.g., 1%, 2%, 3%, and 4%) and thesub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within theindicated range. The statement “about X to Y” has the same meaning as“about X to about Y,” unless indicated otherwise. Likewise, thestatement “about X, Y, or about Z” has the same meaning as “about X,about Y, or about Z,” unless indicated otherwise.

In this document, the terms “a,” “an,” or “the” are used to include oneor more than one unless the context clearly dictates otherwise. The term“or” is used to refer to a nonexclusive “or” unless otherwise indicated.The statement “at least one of A and B” or “at least one of A or B” hasthe same meaning as “A, B, or A and B.” In addition, it is to beunderstood that the phraseology or terminology employed herein, and nototherwise defined, is for the purpose of description only and not oflimitation. Any use of section headings is intended to aid reading ofthe document and is not to be interpreted as limiting; information thatis relevant to a section heading may occur within or outside of thatparticular section.

In the methods described herein, the acts can be carried out in anyorder, except when a temporal or operational sequence is explicitlyrecited. Furthermore, specified acts can be carried out concurrentlyunless explicit claim language recites that they be carried outseparately. For example, a claimed act of doing X and a claimed act ofdoing Y can be conducted simultaneously within a single operation, andthe resulting process will fall within the literal scope of the claimedprocess.

Definitions

The term “about” as used herein can allow for a degree of variability ina value or range, for example, within 10%, within 5%, or within 1% of astated value or of a stated limit of a range, and includes the exactstated value or range.

The term “alkyl” as used herein refers to straight chain and branchedalkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from1 to 8 carbon atoms. Examples of straight chain alkyl groups includethose with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples ofbranched alkyl groups include, but are not limited to, isopropyl,iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompassesn-alkyl, isoalkyl, and anteisoalkyl groups as well as other branchedchain forms of alkyl. Representative substituted alkyl groups can besubstituted one or more times with any of the groups listed herein, forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups.

The term “alkenyl” as used herein refers to straight and branched chainand cyclic alkyl groups as defined herein, except that at least onedouble bond exists between two carbon atoms. Thus, alkenyl groups havefrom 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examplesinclude, but are not limited to vinyl, —CH═C═CCH₂, —CH═CH(CH₃),—CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl,cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienylamong others.

The term “alkoxy” as used herein refers to an oxygen atom connected toan alkyl group, including a cycloalkyl group, as are defined herein.Examples of linear alkoxy groups include but are not limited to methoxy,ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples ofbranched alkoxy include but are not limited to isopropoxy, sec-butoxy,tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclicalkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can includeabout 1 to about 12, about 1 to about 20, or about 1 to about 40 carbonatoms bonded to the oxygen atom, and can further include double ortriple bonds, and can also include heteroatoms. For example, an allyloxygroup or a methoxyethoxy group is also an alkoxy group within themeaning herein, as is a methylenedioxy group in a context where twoadjacent atoms of a structure are substituted therewith.

The term “alkynyl” as used herein refers to straight and branched chainalkyl groups, except that at least one triple bond exists between twocarbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 toabout 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments,from 2 to 8 carbon atoms. Examples include, but are not limited to—C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃), and—CH₂C≡C(CH₂CH₃) among others.

The term “acyl” as used herein refers to a group containing a carbonylmoiety wherein the group is bonded via the carbonyl carbon atom. Thecarbonyl carbon atom is bonded to a hydrogen forming a “formyl” group oris bonded to another carbon atom, which can be part of an alkyl, aryl,aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl group or the like. An acyl group can include0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atomsbonded to the carbonyl group. An acyl group can include double or triplebonds within the meaning herein. An acryloyl group is an example of anacyl group. An acyl group can also include heteroatoms within themeaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example ofan acyl group within the meaning herein. Other examples include acetyl,benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups andthe like. When the group containing the carbon atom that is bonded tothe carbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “aryl” as used herein refers to cyclic aromatic hydrocarbongroups that do not contain heteroatoms in the ring. Thus aryl groupsinclude, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl,indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl,naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.In some embodiments, aryl groups contain about 6 to about 14 carbons inthe ring portions of the groups. Aryl groups can be unsubstituted orsubstituted, as defined herein. Representative substituted aryl groupscan be mono-substituted or substituted more than once, such as, but notlimited to, a phenyl group substituted at any one or more of 2-, 3-, 4-,5-, or 6-positions of the phenyl ring, or a naphthyl group substitutedat any one or more of 2- to 8-positions thereof.

The term “aralkyl” as used herein refers to alkyl groups as definedherein in which a hydrogen or carbon bond of an alkyl group is replacedwith a bond to an aryl group as defined herein. Representative aralkylgroups include benzyl and phenylethyl groups and fused(cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groupsare alkenyl groups as defined herein in which a hydrogen or carbon bondof an alkyl group is replaced with a bond to an aryl group as definedherein.

The term “amine” as used herein refers to primary, secondary, andtertiary amines having, e.g., the formula N(group)₃ wherein each groupcan independently be H or non-H, such as alkyl, aryl, and the like.Amines include but are not limited to R—NH₂, for example, alkylamines,arylamines, alkylarylamines; R₂NH wherein each R is independentlyselected, such as dialkylamines, diarylamines, aralkylamines,heterocyclylamines and the like; and R₃N wherein each R is independentlyselected, such as trialkylamines, dialkylarylamines, alkyldiarylamines,triarylamines, and the like. The term “amine” also includes ammoniumions as used herein. The term “amino group” as used herein refers to asubstituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺, wherein each R isindependently selected, and protonated forms of each, except for —NR₃ ⁺,which cannot be protonated. Accordingly, any compound substituted withan amino group can be viewed as an amine. An “amino group” within themeaning herein can be a primary, secondary, tertiary, or quaternaryamino group. An “alkylamino” group includes a monoalkylamino,dialkylamino, and trialkylamino group.

The term “atm” as used herein refers to a pressure in atmospheres understandard conditions. Thus, 1 atm is a pressure of 101 kPa, 2 atm is apressure of 202 kPa, and so on.

The term “cycloalkyl” as used herein refers to cyclic alkyl groups suchas, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, thecycloalkyl group can have 3 to about 8-12 ring members, whereas in otherembodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or7. Cycloalkyl groups further include polycyclic cycloalkyl groups suchas, but not limited to, norbornyl, adamantyl, bornyl, camphenyl,isocamphenyl, and carenyl groups, and fused rings such as, but notlimited to, decalinyl, and the like. Cycloalkyl groups also includerings that are substituted with straight or branched chain alkyl groupsas defined herein. Representative substituted cycloalkyl groups can bemono-substituted or substituted more than once, such as, but not limitedto, 2,2-, 2,3-, 2,4-2,5- or 2,6-disubstituted cyclohexyl groups ormono-, di- or tri-substituted norbornyl or cycloheptyl groups, which canbe substituted with, for example, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or incombination denotes a cyclic alkenyl group.

The term “deamination” as used herein refers to one or more organicreactions whereby a C—N moiety present in an organic compound isconverted to a C—H moiety. In certain embodiments, the C—N moiety is aprimary amine. In certain embodiments, the primary amine is converted toa diazonium species.

The term “diazotization” as used herein refers to an organic reactionwhereby a primary amine (R—NH₂) is converted to a diazonium species(R—N₂ ⁺). In certain embodiments, the primary amine is reacted with anitrite species, non-limiting examples including t-BuONO and NaNO₂.

The terms “halo,” “halogen,” or “halide” group, as used herein, bythemselves or as part of another substituent, mean, unless otherwisestated, a fluorine, chlorine, bromine, or iodine atom.

The term “haloalkyl” group, as used herein, includes mono-halo alkylgroups, poly-halo alkyl groups wherein all halo atoms can be the same ordifferent, and per-halo alkyl groups, wherein all hydrogen atoms arereplaced by halogen atoms, such as fluoro. Examples of haloalkyl includetrifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl,1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

The term “heteroaryl” as used herein refers to aromatic ring compoundscontaining 5 or more ring members, of which, one or more is a heteroatomsuch as, but not limited to, N, O, and S; for instance, heteroaryl ringscan have 5 to about 8-12 ring members. A heteroaryl group is a varietyof a heterocyclyl group that possesses an aromatic electronic structure.A heteroaryl group designated as a C₂-heteroaryl can be a 5-ring withtwo carbon atoms and three heteroatoms, a 6-ring with two carbon atomsand four heteroatoms and so forth. Likewise a C₄-heteroaryl can be a5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.The number of carbon atoms plus the number of heteroatoms sums up toequal the total number of ring atoms. Heteroaryl groups include, but arenot limited to, groups such as pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl,benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl,benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Heteroaryl groups can be unsubstituted, or can be substitutedwith groups as is discussed herein. Representative substitutedheteroaryl groups can be substituted one or more times with groups suchas those listed herein.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

The term “heterocyclyl” as used herein refers to aromatic andnon-aromatic ring compounds containing three or more ring members, ofwhich one or more is a heteroatom such as, but not limited to, N, O, andS. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, orif polycyclic, any combination thereof. In some embodiments,heterocyclyl groups include 3 to about 20 ring members, whereas othersuch groups have 3 to about 15 ring members. A heterocyclyl groupdesignated as a C₂-heterocyclyl can be a 5-ring with two carbon atomsand three heteroatoms, a 6-ring with two carbon atoms and fourheteroatoms and so forth. Likewise a C₄-heterocyclyl can be a 5-ringwith one heteroatom, a 6-ring with two heteroatoms, and so forth. Thenumber of carbon atoms plus the number of heteroatoms equals the totalnumber of ring atoms. A heterocyclyl ring can also include one or moredouble bonds. A heteroaryl ring is an embodiment of a heterocyclylgroup. The phrase “heterocyclyl group” includes fused ring speciesincluding those that include fused aromatic and non-aromatic groups. Forexample, a dioxolanyl ring and a benzdioxolanyl ring system(methylenedioxyphenyl ring system) are both heterocyclyl groups withinthe meaning herein. The phrase also includes polycyclic ring systemscontaining a heteroatom such as, but not limited to, quinuclidyl.Heterocyclyl groups can be unsubstituted, or can be substituted asdiscussed herein. Heterocyclyl groups include, but are not limited to,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl,dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl,benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Representative substituted heterocyclyl groups can bemono-substituted or substituted more than once, such as, but not limitedto, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with groups such as those listed herein.

The term “heterocyclylalkyl” as used herein refers to alkyl groups asdefined herein in which a hydrogen or carbon bond of an alkyl group asdefined herein is replaced with a bond to a heterocyclyl group asdefined herein. Representative heterocyclyl alkyl groups include, butare not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-ylmethyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

The term “heteroarylalkyl” as used herein refers to alkyl groups asdefined herein in which a hydrogen or carbon bond of an alkyl group isreplaced with a bond to a heteroaryl group as defined herein.

The term “hydrocarbon” or “hydrocarbyl” as used herein refers to amolecule or functional group that includes carbon and hydrogen atoms.The term can also refer to a molecule or functional group that normallyincludes both carbon and hydrogen atoms but wherein all the hydrogenatoms are substituted with other functional groups.

As used herein, the term “hydrocarbyl” refers to a functional groupderived from a straight chain, branched, or cyclic hydrocarbon, and canbe alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combinationthereof. Hydrocarbyl groups can be shown as (C_(a)—C_(b))hydrocarbyl,wherein a and b are integers and mean having any of a to b number ofcarbon atoms. For example, (C₁-C₄)hydrocarbyl means the hydrocarbylgroup can be methyl (C₁), ethyl (C₂), propyl (C₃), or butyl (C₄), and(C₀—C_(b))hydrocarbyl means in certain embodiments there is nohydrocarbyl group.

The term “independently selected from” as used herein refers toreferenced groups being the same, different, or a mixture thereof,unless the context clearly indicates otherwise. Thus, under thisdefinition, the phrase “X¹, X², and X³ are independently selected fromnoble gases” would include the scenario where, for example, X¹, X², andX³ are all the same, where X¹, X², and X³ are all different, where X¹and X² are the same but X³ is different, and other analogouspermutations.

The term “in situ” as used herein refers to the generation of a chemicalentity for use in one or more chemical reactions without purification ofthe chemical species (i.e. in the reaction mixture).

The term “organic group” as used herein refers to any carbon-containingfunctional group. Examples can include an oxygen-containing group suchas an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl)group; a carboxyl group including a carboxylic acid, carboxylate, and acarboxylate ester; a sulfur-containing group such as an alkyl and arylsulfide group; and other heteroatom-containing groups. Non-limitingexamples of organic groups include OR, OOR, OC(O)N(R)₂, CN, CF₃, OCF₃,R, C(O), methylenedioxy, ethylenedioxy, N(R)₂, SR, SOR, SO₂R, SO₂N(R)₂,SO₃R, C(O)R, C(O)C(O)R, C(O)CH₂C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)₂,OC(O)N(R)₂, C(S)N(R)₂, (CH₂)₀₋₂N(R)C(O)R, (CH₂)₀₋₂N(R)N(R)₂,N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)₂, N(R)SO₂R, N(R)SO₂N(R)₂,N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)₂, N(R)C(S)N(R)₂,N(COR)COR, N(OR)R, C(═NH)N(R)₂, C(O)N(OR)R, C(═NOR)R, and substituted orunsubstituted (C₁-C₁₀₀)hydrocarbyl, wherein R can be hydrogen (inexamples that include other carbon atoms) or a carbon-based moiety, andwherein the carbon-based moiety can be substituted or unsubstituted.

The term “room temperature” as used herein refers to a temperature ofabout 15° C. to 28° C.

The term “solvent” as used herein refers to a liquid that can dissolve asolid, liquid, or gas. Non-limiting examples of solvents are silicones,organic compounds, water, alcohols, ionic liquids, and supercriticalfluids.

The term “substantially” as used herein refers to a majority of, ormostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or100%. The term “substantially free of” as used herein can mean havingnone or having a trivial amount of, such that the amount of materialpresent does not affect the material properties of the compositionincluding the material, such that the composition is about 0 wt % toabout 5 wt % of the material, or about 0 wt % to about 1 wt %, or about5 wt % or less, or less than, equal to, or greater than about 4.5 wt %,4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1,0.01, or about 0.001 wt % or less.

The term “substituted” as used herein in conjunction with a molecule oran organic group as defined herein refers to the state in which one ormore hydrogen atoms contained therein are replaced by one or morenon-hydrogen atoms. The term “functional group” or “substituent” as usedherein refers to a group that can be or is substituted onto a moleculeor onto an organic group. Examples of substituents or functional groupsinclude, but are not limited to, a halogen (e.g., F, Cl, Br, and I); anoxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxygroups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groupsincluding carboxylic acids, carboxylates, and carboxylate esters; asulfur atom in groups such as thiol groups, alkyl and aryl sulfidegroups, sulfoxide groups, sulfone groups, sulfonyl groups, andsulfonamide groups; a nitrogen atom in groups such as amines,hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, andenamines; and other heteroatoms in various other groups. Non-limitingexamples of substituents that can be bonded to a substituted carbon (orother) atom include F, Cl, Br, I, OR, OC(O)N(R)₂, CN, NO, NO₂, ONO₂,azido, CF₃, OCF₃, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy,ethylenedioxy, N(R)₂, SR, SOR, SO₂R, SO₂N(R)₂, SO₃R, C(O)R, C(O)C(O)R,C(O)CH₂C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)₂, OC(O)N(R)₂, C(S)N(R)₂,(CH₂)₀₋₂N(R)C(O)R, (CH₂)₀₋₂N(R)N(R)₂, N(R)N(R)C(O)R, N(R)N(R)C(O)OR,N(R)N(R)CON(R)₂, N(R)SO₂R, N(R)SO₂N(R)₂, N(R)C(O)OR, N(R)C(O)R,N(R)C(S)R, N(R)C(O)N(R)₂, N(R)C(S)N(R)₂, N(COR)COR, N(OR)R, C(═NH)N(R)₂,C(O)N(OR)R, and C(═NOR)R, wherein R can be hydrogen or a carbon-basedmoiety; for example, R can be hydrogen, (C₁-C₁₀₀)hydrocarbyl, alkyl,acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, orheteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or toadjacent nitrogen atoms can together with the nitrogen atom or atomsform a heterocyclyl.

Compounds

Phebox ligands are useful for a number of catalytic transformations oforganic molecules, including transformations of alkanes generallyrequiring harsh conditions. Since catalytic transformations using thisclass of ligands intrinsically involve the activation of C—H bonds, thedegradation of the phebox ligand via reactions of the C—H bonds of thearyl position (benzylic or aryl C—H bonds) is potentially problematic.It is therefore sought herein to protect these positions with specificgroups, such as but not limited to —CF₃ groups.

In one aspect, a compound of formula (I), or a salt or solvate thereof,is:

wherein:

-   -   R¹ and R² are each CH₃, or R¹ and R² taken together are —(CH₂)₄—        or —(CH₂)₅—;    -   R³ is selected from the group consisting of CF₃, CF₂CF₃, CN, and        NO₂;    -   R⁴ is selected from the group consisting of CF₃, CF₂CF₃, CN, and        NO₂;    -   R⁵ is selected from the group consisting of H, CF₃, CF₂CF₃, CN,        and NO₂, and    -   E is CH or N.

In certain embodiments, R¹ and R² are each CH₃.

In certain embodiments, R³ and R⁴ are each CF₃.

In certain embodiments, E is CH.

In certain embodiments, the compound of formula (I) is selected from thegroup consisting of

In certain embodiments, the compound of formula (I) is selected from thegroup consisting of

The compounds described herein can possess one or more stereocenters,and each stereocenter can exist independently in either the (R) or (S)configuration. In certain embodiments, compounds described herein arepresent in optically active or racemic forms. It is to be understoodthat the compounds described herein encompass racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.Preparation of optically active forms is achieved in any suitablemanner, including by way of non-limiting example, by resolution of theracemic form with recrystallization techniques, synthesis fromoptically-active starting materials, chiral synthesis, orchromatographic separation using a chiral stationary phase. In certainembodiments, a mixture of one or more isomer is utilized as thetherapeutic compound described herein. In other embodiments, compoundsdescribed herein contain one or more chiral centers. These compounds areprepared by any means, including stereoselective synthesis,enantioselective synthesis and/or separation of a mixture of enantiomersand/or diastereomers. Resolution of compounds and isomers thereof isachieved by any means including, by way of non-limiting example,chemical processes, enzymatic processes, fractional crystallization,distillation, and chromatography.

In certain embodiments, the compound(s) described herein can exist astautomers. All tautomers are included within the scope of the compoundspresented herein.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser & Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey & Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts,Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all ofwhich are incorporated by reference for such disclosure). Generalmethods for the preparation of compound as described herein are modifiedby the use of appropriate reagents and conditions, for the introductionof the various moieties found in the formula as provided herein.

Methods of Making Compounds of Formula (I)

In another aspect, a method of making the compound of formula (I) isprovided. The method comprises:

-   -   converting

-   -   into

-   -   and    -   contacting

-   -   with

-   -   to provide the compound of formula (I).

In certain embodiments, converting compounds of formula (II) tocompounds of formula (V) comprises:

-   -   brominating

-   -   to provide

-   -   deaminating

-   -   to provide

-   -   cyanating

-   -   to provide

In certain embodiments, brominating comprises contacting FeBr₃ with thecompound of formula (II). In certain embodiment, the compound of formula(II) is 3,5-bis(trifluoromethyl)aniline having formula

and the bromination can be performed as shown in Scheme 1.

In certain embodiments, FeBr₃ can be generated in situ before additionof the aniline to the reaction system. The reaction is scalable and canbe performed up to, for example, 30 mmol scale in at least about 90%yield or higher to obtain 2,6-dibromo-3,5-bis(trifluoromethyl)aniline(Ma). In various embodiments, the compound of formula (II) contacts theFeBr₃ after the generation of FeBr₃ is completed.

In certain embodiments, the purification of (Ma) is performed usingflash column chromatography.

In certain embodiments, the deamination of compound of formula (III)occurs via diazotization and warming. In certain embodiments, warmingcan include letting the reaction come up to room temperature on its own.

In certain embodiments, the compound of formula (III) is2,6-dibromo-3,5-bis(trifluoromethyl)aniline having formula (Ma), and thedeamination can be performed as shown in Scheme 2.

Deamination of (Ma) is performed using a diazonium salt formationprocedure. Under the reaction conditions used, in certain embodimentsthe deaminated product—1,5-dibromo-2,4-bis(trifluoromethyl)benzenehaving formula (IVa) is isolated, suggesting that the desired diazomiumsalt is fairly unstable under the reaction conditions. Without wishingto be limited by any theory, this reaction may occur through a radicalmechanism that results in formation of the deaminated product. Thedeamination reaction is easily scalable.

In certain embodiments, cyanating of the compound of formula (IV)comprises contacting the compound of formula (IV) with a transitionmetal cyanide.

In certain embodiments, the compound of formula (IV) is1,5-dibromo-2,4-bis(trifluoromethyl)benzene, having formula (IVa), thetransition metal cyanide is CuCN, and the cyanation reaction isperformed as shown in Scheme 3 to obtain1,5-bis(cyano)-2,4-bis(trifluoromethyl)benzene, having formula (Va).

The cyanation product can be obtained by purification of the reactionmixture by column chromatography, for example.

In certain embodiments, the compound of formula (V) is contacted withthe compound of formula (VI) in the presence of a Lewis acid to obtainthe Phebox ligand. In certain embodiments, the Lewis acid is Zn(OTf)₂.

In certain embodiments, the compound of formula (V) is1,5-bis(cyano)-2,4-bis(trifluoromethyl)benzene, having formula (Va), andit is reacted with 2-amino-3-hydroxy-2-methyl-propane (VIa) underWitte-Seeliger conditions to yield a bis-CF₃-Phebox ligand (VIIa)(Scheme 4).

In certain embodiments, the Witte-Seeliger reaction is performed in asealed flask over the period of about 2, 3, 4, or about 5 d.

Compounds described herein are synthesized using any suitable proceduresstarting from compounds that are available from commercial sources, orare prepared using procedures described herein.

EXAMPLES

The disclosure further describes additional details by reference to thefollowing experimental examples. These examples are provided forpurposes of illustration only, and are not intended to be limitingunless otherwise specified. Thus, the disclosure should in no way beconstrued as being limited to the following examples, but rather, shouldbe construed to encompass any and all variations which become evident asa result of the teaching provided herein.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentdisclosure and practice the claimed methods. The following workingexamples therefore, specifically point out the preferred embodiments ofthe disclosure, and are not to be construed as limiting in any way theremainder of the disclosure.

Example 1: Synthesis of Phebox Ligand Synthesis of Compound(IIIa)—2,6-dibromo-3,5-bis(trifluoromethyl)aniline

Iron powder (280 mg, 5.01 mmol, 0.5 equiv), sodium carbonate (1.075 g,10.14 mmol, 1 equiv), and dichloromethane (50 mL) were added to a roundbottomed flask equipped with a stir bar. Bromine (1.55 mL, 30.1 mmol, 3equiv) was added to the mixture via syringe to give a dark red mixturewhich was stirred for 30 min. 3,5-bis(trifluoromethyl)aniline (1.57 mL,10.0 mmol, 1 equiv) was added via syringe. The flask was equipped with areflux condenser, and the dark red mixture was heated to reflux. Thereaction was monitored by TLC in 10% EtOAc/hexanes (v:v) where the R_(f)of the product is 0.4. After 3.5 d, the dark red mixture was cooled toroom temperature and was treated with saturated sodium carbonate (200mL) to give an orange biphasic mixture. The organic layer was separatedin a separatory funnel, and the aqueous layer was extracted with DCM(3×30 mL) and Et₂O (2×30 mL). The organic extracts were dried with MgSO₄and were filtered through glasswool to give a light orange solution. Thevolatile components were removed under educed pressure to give a lightorange residue. The product was purified by flash column chromatographyusing 250 g of silica gel and 10% EtOAc/hexanes (v:v). The productfractions were combined and the volatile components were removed underreduced pressure to give the product as a semi-crystalline off-whitesolid (3.74 g, 96.8% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.37 (s, 1H),5.24 (s, 2H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 109.5, 114.3 (m,J_(CF)=6 Hz), 121.1 (q, J_(CF)=272 Hz), 130.1 (q, J_(CF)=32 Hz), 145.5ppm. ¹⁹F{¹H} NMR (282.2 MHz, CDCl₃): δ −63.5 (s) ppm.

Synthesis of Compound (IVa)—1,5-dibromo-2,4-bis(trifluoromethyl)benzene

Schlenk techniques under Ar were used for this procedure.2,6-dibromo-3,5-bis(trifluoromethyl)aniline (2.902 g, 7.5 mmol) wasadded to a Schlenk flask along with dry THF (33 mL). The colorlesssolution was cooled to −8° C. (T was maintained between −6° C. and −8°C.) in an ice bath. BF₃ etherate (1.7 mL, 13.7 mmol) was added viasyringe and no change was observed. After 5 min, tert-butyl nitrite (1.4mL, 11.8 mmol) was added to the solution via syringe and no change wasobserved. After 1 h, a bright yellow solution was observed and T=−6° C.The solution was allowed to slowly warm overnight in the ice bath. After19 h, a bright orange solution was observed and T=17 C. TLC (10%EtOAc/hexanes) was performed and no starting material was observed. Thevolatile components were removed by evaporation aided by compressed airto give an oily red-brown residue. The residue was purified via columnchromatography using 125 g of silica gel, 10% EtOAc/hexanes, and 25 mLfractions. The product fractions were combined and the volatilecomponents were removed by evaporation aided by compressed air. Theoff-white solid was then dried under high vacuum to give 1.530 g ofproduct (54.9% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.12 (s, 1H), 7.95 (s,1H) ppm. ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 123.3 (q, J_(CF)=272.5 Hz),124.9 (m, J_(CF)=1 Hz), 126.9 (sep, J_(CF)=5 Hz), 130.1 (q, J_(CF)=32.5Hz), 141.02 ppm. ¹⁹F{¹H} NMR (470.4 MHz, CDCl₃): δ −63.40 (s) ppm.

Synthesis of Compound(Va)—1,5-bis(cyano)-2,4-bis(trifluoromethyl)benzene

Schlenk techniques under Ar were used for this procedure. CuCN (230 mg,2.57 mmol) was added as a solid to a small bomb flask.1,5-dibromo-2,4-bis(trifluoromethyl)benzene (373 mg, 1.0 mmol) wasweighed into a small vial. The organic starting material was transferredquantitatively using dry DMF (5 mL) to the bomb flask. The flask wassealed and the mixture was heated at 150° C. After 21 h, the orangemixture with white precipitate was cooled to room temperature. TLC (20%EtOAc/hexanes) was performed and no starting material was observed. Themixture was transferred to a small Schlenk flask and the volatilecomponents were removed under reduced pressure to give a brown residue.The residue was purified via column chromatography using 20 g of silicagel, 20% EtOAc/hexanes, and 10 mL fractions. The product fractions werecombined and the volatile components were removed under reduced pressureto give the product as a pale light yellow powder (209 mg, 79.2%). ¹HNMR (500 MHz, CDCl₃): δ 8.32 (s, 1H), 8.23 (s, 1H) ppm. ¹³C{¹H} NMR (125MHz, CDCl₃): δ 112.39, 115.31, 122.0 (q, J_(CF)=273.8 Hz), 125.6 (sep,J_(CF)=5 Hz), 137.2 (q, J_(CF)=35 Hz), 140.12 ppm. ¹⁹F{¹H} NMR (470.4MHz, CDCl₃): δ −62.82 (s) ppm.

Synthesis of Compound (VIIa)—bis-CF₃-Phebox

Schlenk techniques under Ar were used for this procedure.1,5-bis(cyano)-2,4-bis(trifluoromethyl)benzene (129 mg, 0.488 mmol) andZn(OTf)₂ (18.4 mg, 0.051 mmol) were added as solids to a small bombflask. β-xylene (2.5 mL) was added to give a clear mixture. Theamino-alcohol (0.10 mL, 1.05 mmol) was added as a liquid via syringe.The flask was sealed and the mixture was heated at 150° C. for 5 d.

Enumerated Embodiments

The following exemplary embodiments are provided, the numbering of whichis not to be construed as designating levels of importance:

Embodiment 1 provides a compound of formula (I), or a salt or solvatethereof:

wherein:

-   -   R¹ and R² are each CH₃, or R¹ and R² taken together are —(CH₂)₄—        or —(CH₂)₅—;    -   R³ is selected from the group consisting of CF₃, CF₂CF₃, CN, and        NO₂;    -   R⁴ is selected from the group consisting of CF₃, CF₂CF₃, CN, and        NO₂;    -   R⁵ is selected from the group consisting of H, CF₃, CF₂CF₃, CN,        and NO₂, and    -   E is CH or N.

Embodiment 2 provides the compound of Embodiment 1, wherein R¹ and R²are CH₃.

Embodiment 3 provides the compound of any of Embodiments 1-2, wherein R³and R⁴ are CF₃.

Embodiment 4 provides the compound of any of Embodiments 1-3, wherein Eis CH.

Embodiment 5 provides the compound of any of Embodiments 1-4, whereinthe compound is

Embodiment 6 provides a method of making the compound of any ofEmbodiments 1-5, the method comprising:

-   -   converting

-   -   into

-   -   and    -   contacting

-   -   with

-   -   to provide the compound of formula (I).

Embodiment 7 provides the method of Embodiment 6, wherein converting(II) to (V) comprises:

-   -   brominating

-   -   to provide

-   -   deaminating

-   -   to provide

-   -   cyanating

-   -   to provide

Embodiment 8 provides the method of any of Embodiments 6-7, whereinbrominating comprises contacting FeBr₃ with the compound of formula(II).

Embodiment 9 provides the method of any of Embodiments 6-8, wherein theFeBr₃ is generated in situ.

Embodiment 10 provides the method of any of Embodiments 6-9, wherein thecompound of formula (II) contacts the FeBr₃ after the FeBr₃ isgenerated.

Embodiment 11 provides the method of any of Embodiments 6-10, whereinthe deaminating of compound of formula (III) occurs via diazotizationand warming.

Embodiment 12 provides the method of any of Embodiments 6-11, whereinthe cyanating of the compound of formula (IV) comprises contacting thecompound of formula (IV) with a cyanide salt.

Embodiment 13 provides the method of any of Embodiments 6-12, whereinthe cyanide salt is a transition metal cyanide salt.

Embodiment 14 provides the method of any of Embodiments 6-13, whereinthe transition metal cyanide salt is CuCN.

Embodiment 15 provides the method of any of Embodiments 6-14, whereinthe compound of formula (V) is contacted with the compound of formula(VI) in the presence of a Lewis acid.

Embodiment 16 provides the method of any of Embodiments 6-15, whereinthe Lewis acid is Zn(OTf)₂.

Other Embodiments

The recitation of a listing of elements in any definition of a variableherein includes definitions of that variable as any single element orcombination (or subcombination) of listed elements. The recitation of anembodiment herein includes that embodiment as any single embodiment orin combination with any other embodiments or portions thereof.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety. While this disclosure herein has been presented withreference to specific embodiments, it is apparent that other embodimentsand variations of this disclosure may be devised by others skilled inthe art without departing from the true spirit and scope of thisdisclosure. The appended claims are intended to be construed to includeall such embodiments and equivalent variations.

What is claimed is:
 1. A compound of formula (I), or a salt or solvatethereof:

wherein: R¹ and R² are each CH₃, or R¹ and R² taken together are—(CH₂)₄— or —(CH₂)₅—; R³ is selected from the group consisting of CF₃,CF₂CF₃, CN, and NO₂; R⁴ is selected from the group consisting of CF₃,CF₂CF₃, CN, and NO₂; R⁵ is selected from the group consisting of H, CF₃,CF₂CF₃, CN, and NO₂, and E is CH or N.
 2. The compound of claim 1,wherein R¹ and R² are each CH₃.
 3. The compound of claim 1, wherein R³and R⁴ are each CF₃.
 4. The compound of claim 1, wherein E is CH.
 5. Thecompound of claim 1, wherein the compound is


6. A method of making the compound of claim 1, the method comprising:converting

into

and contacting

with

to provide the compound of formula (I).
 7. The method of claim 6,wherein converting (II) to (V) comprises: a) brominating

to provide

b) deaminating

to provide

c) cyanating

to provide


8. The method of claim 7, wherein brominating comprises contacting FeBr₃with the compound of formula (II).
 9. The method of claim 8, wherein theFeBr₃ is generated in situ.
 10. The method of claim 9, wherein thecompound of formula (II) contacts the FeBr₃ after the FeBr₃ isgenerated.
 11. The method of claim 7, wherein the deaminating ofcompound of formula (III) occurs via diazotization and warming.
 12. Themethod of claim 7, wherein monocyanation of the compound of formula (IV)comprises contacting the compound with a cyanide salt.
 13. The method ofclaim 12, wherein the cyanide salt is a transition metal cyanide salt.14. The method of claim 13, wherein the transition metal cyanide salt isCuCN.
 15. The method of claim 6, wherein the compound of formula (V) iscontacted with the compound of formula (VI) in the presence of a Lewisacid.
 16. The method of claim 15, wherein the Lewis acid is Zn(OTf)₂.